The present invention is concerned with compounds and their pharmaceutically acceptable salts which have anti-viral activity, particularly activity against retroviruses including human immunodeficiency virus (HIV). The compounds of the present invention also act as immunomodulators. It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of viral infections and AIDS.
Retroviruses refer to a family of viruses which have RNA as their genetic material and also the enzyme reverse transcriptase (RNA-dependent DNA polymerase), of which the latter is essential for self-replication by synthesizing complementary DNA on the template RNA of the virus.
Retroviruses include various oncoviruses such as avian leukemia virus, avian sarcoma virus, avian reticuloendotheliosis virus, murine mammary cancer virus, murine leukemia virus, murine sarcoma virus, quinea pig type C virus, hamster type C virus, rat leukemia virus, feline leukemia virus, feline sarcoma virus, feline type C virus, ovine leukemia virus, bovine leukemia virus, swine type C virus, simian leukemia virus, Mason-Pfizer virus, simian sarcoma virus, simian T-lymphotropic virus, baboon type C virus, and the like. Among those infective to humans, those important are adult T-cell leukemia virus (ATLV), or human T-lymphotropic virus type I (HTLV-I) and type II (HTLV-II).
On the other hand, retroviruses also include those having no oncogenicity, such as visna virus, ovine progressive pneumonia virus, ovine maedi virus, simian T-lymphotropic virus type III (STLV-III), equine infectious anemia virus, and the like. The viruses isolated from humans as causitive agents for AIDS, ARC, PGL and LAS (so called AIDS-viruses such as HTLV-III, LAV1, LAV2, ARV and HTLV-IV) belong to this subfamily. Recently, AIDS-causative viruses are called HIVs.
Spumavirane, a subfamily of retroviruses, includes simian foaming virus. Also, a retrovirus has been recently isolated as a causative virus for Kawasaki disease (mucocutaneous lymphonode syndrome).
Hepatitis B virus (HBV) is a DNA virus with a unique circular double-stranded DNA genome which is partly single-stranded. It contains a specific DNA polymerase required for viral replication. This DNA polymerase also acts as a reverse transcriptase during the replication of HBV DNA via an RNA intermediate.
2',3'-Dideoxynucleosides and 2',3'-dideoxy-2',3'-didehydronucleosides have been shown to be effective as antiviral agents, particularly against HIV. (E. De Clercq, Adv. Druo Res., 17, 1 (1988)) 3-Deazaadenosine has also been shown to be effective as an antiviral agent (G. L. Cantoni, et al., U.S. Pat. No. 4,148,888; C. M. Stoltzfus and J. A. Montgomery, J. Vir., 38, 173 (1981); A. J. Bodner, et al., Biochem. and Biophys. Res. Comm., 98, 476 (1981)). The antiviral potential of 3-deazaadenosine has been ascribed to the compound's role as both a potent inhibitor of S-adenosylhomocysteine hydrolase and as a substrate for the same enzyme. Such a method of action causes undesirable side effects, such as general cytotoxicity.
3-Deazaadenosine and its derivatives have also been shown to inhibit the immune response and to possess antiinflamatory activity (U.S. Pat. No. 4,309,419). Similar antiinflamatory and immunosuppressant activity has been disclosed for certain 2'-deoxynucleosides (E.P. Application 0 038 569).
3-Deazaadenosine, 2',3'-dideoxynucleosides and related compounds undergo facile in vivo metabolic cleavage of their glycosyl bond, which effectively inactivates their biological potency. Adenosine derivatives such as those disclosed in U.S. Pat. No. 4,148,888 are also catabolized in vivo by deaminase enzymes.
The compounds of the instant invention retain the antiviral and immunosuppressant potency present in the nucleoside compounds that have been previously disclosed. However, unlike the previously disclosed agents, the compounds of the instant invention are not susceptable to acid or enzymatic cleavage of the labile glycosyl group.
A further advantage of the compounds of the instant invention is that they have antiviral potency without inhibiting or acting as a substrate for S-adenosylhomocysteine hydrolayse.